Sunday, March 19, 2006

Medical Abortion Deaths

Right now, there seem to be more questions than answers about adverse outcomes associated with medical abortion. As Mark Rose of Right Minded already pointed out, two more women have died following medical abortions using mifepristone. Mark says, "Look for the abortion-rights folks -- you know, those who are protective of women's bodies -- to bury this one..." Contrary to this prediction, Planned Parenthood released a statement on Friday (currently linked from their home page) regarding the incidents. PPFA has responded by changing their protocol, stating, "Our health centers will no longer recommend the option of administering misoprostol vaginally (misoprostol is the second drug in the two-drug medication abortion regimen). Patients will now receive misoprostol orally or buccally (where the pill is placed between the cheek and gum and dissolves). This change in protocol is effective immediately." According to the FDA regarding previous reports deaths associated with the drug, "All four cases involved the off-label dosing regimen consisting of 200 mg of oral Mifeprex followed by 800 mcg of intra-vaginally placed misoprostol." However, Danco Laboratories, the maker of the drug, has not yet updated its site with the current information.

This is an interesting story on several points. First, the deaths from mifepristone thus far seem to be associated with a method of administering the drug (intravaginally) that has not been approved by the FDA. The FDA does not prohibit off-label use of drugs, but says, "If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects." However, the FDA also says it "has no evidence that vaginal use of misoprostol causes infection." Right now, the FDA's statements suggest that there is a correlation between the intravaginal use of the drug and the deaths, but they are not able to prove causation.

So, what information led prescribers to use the drug intra-vaginally? Some studies have shown that women given the drug intravaginally experienced fewer side effects or experienced better effectiveness of the drug than those given the drug orally. Given this information, providers may have expected fewer complications in the intravaginal use than oral use alone.

Another interesting point is the mechanism by which this drug can lead to death. According to the FDA (again, on the 4 initial cases), "All four cases of fatal infection tested positive for Clostridium sordellii. In addition, FDA tested drug from manufacturing lots of mifepristone and misoprostol and found no contamination with Clostridium sordellii." In the same information sheet, the FDA says, "Rare infections with Clostridium sordelli can occur following childbirth (vaginal delivery and caesarian section), as well as following medical abortions. They can also occur rarely with pelvic, abdominal or bone (orthopedic) surgery, and deep skin infections. The bacteria may also be present in women’s intestinal and rectal areas and cause no symptoms whatsoever, not producing any toxins. This is called 'colonization' and is not known to be a health problem. It is unclear exactly what factors cause the bacteria to produce the toxins in women." Essentially, the FDA is saying that each woman tested positive for the bacteria, infection can occur either with medical abortion, vaginal birth, or c-section, and it's not proven that intravaginal use was the cause. It seems that we need a bit more information on what exactly is going on in these cases. With better understanding of how the toxin is produced and individual risk factors, providers should be able to make better decisions with their patients.

The third point that I've seen little discussion of is how dangerous this drug is compared to surgical abortion or childbirth, or compared to other drugs. The FDA states, "Reports of fatal sepsis in women undergoing medical abortion are very rare (approximately 1 in 100,000)." This table from the 2005 Health, United States report lists the 2002 maternal mortality rate as 7.6 per 100,000 live births. This would suggest that of 100,000 women who either have medical abortion or a live birth, live birth is more deadly to women, although more information is likely needed. Information on mortality rates for other prescription drugs was not readily available, but would be interesting to compare.

5 Comments:

The treatment for endo interests me. There has been not a lot of new ground in endo treatment, and until the new gene therapy stuff comes on line we're still stuck with the hormonal end-runs like Lupron.

Thanks. I did some more sleuthing, and it looks like they'd be using it as just another hormonal end-run. Instead of supressing both estrogen and progesterone (like Lupron), mife.... would be a progesterone-only suppression.

May work for some, but I'd sure like to see something where the "cure" isn't worse than the disease.

"Mifepristone (formerly known as RU 486) is a safe, effective, non-surgical form of early abortion which is now available in several countries, including France, Great Britain, Sweden and, as of September 28, 2000, the United States.

Mifepristone blocks the action of progesterone, a hormone necessary to sustain pregnancy. Mifepristone is used in combination with a prostaglandin called misoprostol.

Mifepristone has already been successfully used by millions of women worldwide as a method of early abortion, and may be a possible treatment for fibroid tumors, ovarian cancer, endometriosis, meningioma, and some types of breast cancer.... .

I hope we see some more in the way of clinical trials for the drugs uses. It's been difficult due to the controversy surrounding the drug but it's uses are plentiful. I can share the following with you and more detail via each link:

Reproductive biology and endocrinology study:http://www.pubmedcentral.gov/articlerender.fcgi?artid=165445• “RU486 crosses the blood-brain-barrier and is present at only 28% of levels seen in the serum [75]. Perhaps glial development would be further improved in the presence of higher levels of RU486....”

1992: Mifepristone (RU 486) treatment of meningiomas.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=1619417&dopt=Citation• “Mifepristone treatment resulted in control of tumor growth (stable disease) in 6 of 10 patients who had shown recent evidence of tumor growth. In 3 of these 6 patients, consistent tumor shrinkage was seen. author's modified,”

1993: Inhibition of growth of the human malignant glioma cell line (U87MG) by the steroid hormone antagonist RU486http://jcem.endojournals.org/cgi/content/abstract/77/5/1388• “These results indicate that the growth of U87MG human malignant glioma is dependent on corticoids. The antiproliferative effect of RU486 appears to be due to the inhibition of binding of glucocorticoid hormones to their receptor proteins. Our results suggest a new therapy for some brain tumors, such as malignant gliomas based on the steroid hormone antagonist RU486.”

1993: Regression of uterine leiomyomata in response to the anti-progesterone RU486http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8432797&dopt=Abstract• “RU 486 proved to be safe and effective for a novel mode of management for uterine leiomyomata.”

1995: Regression of uterine leiomyomata to the antiprogesterone RU486: dose response effecthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7789557&dopt=Abstract• “Administration of 5 mg of RU486 decreases leiomyomata volume to 80.6% of baseline at 4 weeks, 63.7% at 8 weeks, and 74.4% after 12 weeks of treatment. 25 mg daily appears to be the effective dose to cause a clinically significant 50% decrease in leiomyomata volume.”

1995: Growth inhibition of androgen-insensitive human prostate carcinoma cells by a 19-norsteroid derivative agent, mifepristone.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7716084&dopt=Abstract• “In conclusion, our results demonstrated that the growth of androgen-insensitive prostate cancer cells can be directly inhibited by mifepristone in cultures. This in vitro inhibition is reflected in xenografted tumors.”

1996: Inhibition of P-glycoprotein activity in human leukemic cells by mifepristone.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8913436• “These results thus indicate that mifepristone can strongly inhibit P-gp activity in human cells, including tumoral cells freshly isolated from patients, therefore suggesting that the clinical use of this compound may contribute to down-modulate P-gp-mediated drug resistance.”

1998 - Additive effect of mifepristone and tamoxifen on apoptotic pathways in MCF-7 human breast cancer cells:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9879777&dopt=Abstract• “Our data further suggest that a combination of an antiprogestin with tamoxifen may be more effective than tamoxifen monotherapy in the management of human breast cancer.”

1999: Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10427136&dopt=Abstract• “The anti-progestine, RU486, also blocked glucosylceramide synthesis in cells; however, LY117018, a raloxifene analog, was without influence. We propose that an enhanced capacity to glycosylate ceramide as evidenced in MCF-7-AdrR cells, is a molecular determinant of drug resistance, particularly as regards resistance to ceramide-enhancing agents such as anthracyclines, ionizing radiation, and tumor necrosis factor-alpha.”

1999: Reversal of MRP-mediated multidrug resistance in human lung cancer cells by the antiprogestatin drug RU486.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10329417&dopt=Abstract• “These findings therefore demonstrate that RU486 can down-modulate MRP-mediated drug resistance, in addition to that linked to P-gp, through inhibition of MRP function.”

2000: Phase II study of mifepristone (RU486) in refractory ovarian cancer.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10831354&dopt=Abstract• “Mifepristone has activity against ovarian cancer resistant to cisplatin and paclitaxel. The drug is well tolerated. Further studies need to be performed when this drug becomes more widely available in the United States.”

2000: RU486 increases radiosensitivity and restores apoptosis through modulation of HPV E6/E7 in dexamethasone-treated cervical carcinoma cells http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10739708&dopt=Abstract• “RU486 reverses glucocorticoid-dependent upregulation of HPV E6/E7, which corresponds to restoration of p53 expression, and restores radiosensitivity and apoptosis following gamma-irradiation. Therefore, it appears that along with radiation, RU486 may be a beneficial agent in the treatment of hormone-reactive cervical tumors.”

2000: Antitumor activity of mifepristone in the human LNCaP, LNCaP-C4, and LNCaP-C4-2 prostate cancer models in nude mice.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10617866&dopt=Abstract• “This is the first report demonstrating significant antitumor activity of mifepristone in both androgen-sensitive and androgen-insensitive variants of the LNCaP human prostate cancer model in nude mice. These results suggest a potential clinical benefit of the use of antiprogestins as a novel nonandrogen ablation therapeutic approach in the management of prostate cancer.”

2001: Differential Expression of Members of the Tumor Necrosis Factor -related Apoptosis-inducing Ligand Pathway in Prostate Cancer Cellshttp://cancerres.aacrjournals.org/cgi/content/abstract/61/19/7179• “The involvement of the TRAIL pathway was further confirmed by the activation of caspase-8 in Mifepristone-treated cells. This was followed by truncation of Bid, confirming that Mifepristone activates the TRAIL pathway. This knowledge is being used to design a combination treatment of TRAIL and Mifepristone to induce significant apoptosis in prostate cancer cells.”

2002: Mifepristone Pretreatment Overcomes Resistance of Prostate Cancer Cells to Tumor Necrosis Factor -related Apoptosis-inducing Ligand (TRAIL) http://mct.aacrjournals.org/cgi/content/abstract/1/10/831• “Examination of the effects of TRAIL (tumor necrosis factor -related apoptosis-inducing ligand) showed higher apoptotic response in LNCaP C4-2, whereas LNCaP were resistant. However, treatment of LNCaP with Mifepristone, an antiprogestin, before TRAIL induced significant apoptosis, similar to the levels observed in LNCaP C4-2.... On the basis of our results, it is suggested that the differences in response of the two cell lines to TRAIL is at the mitochondrial level.”

2003: Study of effect of mifepristone on apoptosis of human ovarian cancer cell line 3AOhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=14728868&dopt=Abstract• “Mifepristone inhibited significantly the proliferation and induced the cell apoptosis of cell line 3AO in dose-time dependent manner in vitro. The anti-tumor effect was related to down-regulation the expression of PR protein and bcl-2 protein, and to up-regulation the expression of p53 protein of 3AO cells.”

2003: Enhancement of antitumor effect of cisplatin against human ovarian carcinoma cells by mifepristone in vivo.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12651241&dopt=Abstract• “At a non-toxic dose, RU486 may enhance the sensitivity of tumor cells to cisplatin in vivo, possibly through the mechanism of inhibiting GcS expression at the mRNA level.”

2003 - Study on the treatment of high dose mifepristone and progesterone in endometrial carcinomahttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14680611&dopt=Abstract• “The study indicates that high dose progesterone could inhibit the growth, promote apoptosis and inhibit metastasis of endometrial carcinoma, MIF could inhibit the growth and promote apoptosis, MIF + MPA could more strongly inhibit the growth, promote apoptosis and inhibit metastasis of endometrial carcinoma than MIF or MPA, and synergistic effect was observed on the expression of PCNA, ER, PR, bax and bcl-2.”

2003: Antiandrogen Effects of Mifepristone on Coactivator and Corepressor Interactions with the Androgen Receptorhttp://mend.endojournals.org/cgi/content/abstract/18/1/70• “Finally, mifepristone at high concentrations induced a low level of prostate-specific antigen expression in LNCaP and antagonized prostate-specific antigen expression induced by R1881. Mifepristone also antagonized R1881 action on the growth of LNCaP prostate cancer cells.”

2004: Effects of mifepristone on proliferation of human gastric adenocarcinoma cell line SGC-7901 in vitro.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15309708&itool=iconfft&query_hl=20&itool=pubmed_docsum• “Mifepristone effectively inhibited the proliferation of PR-positive human gastric adenocarcinoma cell line SGC-7901 in vitro through multiple mechanisms, and may be a beneficial agent against human adenocarcinoma”

2004: Reversal of multidrug resistance in drug-resistant human gastric cancer cell line SGC7901/VCR by antiprogestin drug mifepristonehttp://www.wjgnet.com/1007-9327/abstract_en.asp?v=10&f=1722• “Mifepristone has potent reversal effect on MDR in SGC7901/VCR via inhibiting the function of MRP and P-gp, modulating the expression of Bcl-2 and Bax proteins, and enhancing the sensitivity to anticancer agent VCR.”

2004: Effects of mifepristone on proliferation of human gastric adenocarcinoma cell line SGC-7901 in vitro.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15309708&itool=iconfft&query_hl=20&itool=pubmed_docsum• “Mifepristone effectively inhibited the proliferation of PR-positive human gastric adenocarcinoma cell line SGC-7901 in vitro through multiple mechanisms, and may be a beneficial agent against human adenocarcinoma.”

2004: Inhibitory effects of mifepristone on the growth of human gastric cancer cell line MKN-45 in vitro and in vivo.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15669177&itool=iconabstr&query_hl=20&itool=pubmed_docsum• “Mifepristone exerts significant growth inhibitory effects on PR-positive human MKN-45 gastric cancer cells via multiple mechanisms, and may be a beneficial agent against the tumor.”

2004: Effects of mifepristone on invasive and metastatic potential of human gastric adenocarcinoma cell line MKN-45 in vitro and in vivo.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15188494&dopt=• “Mifepristone can effectively inhibit the invasive and metastatic potential of human gastric adenocarcinoma cell line MKN-45 in vitro and in vivo through inhibition of heterotypic adhesion to basement membrane, cell migration and angiogenesis.”

2004: Mifepristone Induces Growth Arrest, Caspase Activation, and Apoptosis of Estrogen Receptor-Expressing, Antiestrogen-Resistant Breast Cancer Cellshttp://clincancerres.aacrjournals.org/cgi/content/abstract/10/15/5215• “We demonstrate that: (a) estrogen receptor+progesterone receptor+, 4-OHT-resistant clonal variants can be isolated from an MCF-7 cell line in the absence of antiestrogen selection; and (b) MIF and MIF plus 4-OHT combination therapy induces growth arrest and active cell death of the antiestrogen-resistant breast cancer cells. These preclinical findings show potential for a combined hormonal regimen of an antiestrogen and an antiprogestin to combat the emergence of antiestrogen-resistant breast cancer cells and, ultimately, improve the therapeutic index of antiestrogen therapy.”

2005: The androgen receptor recruits nuclear receptor CoRepressor (N-CoR) in the presence of mifepristone via its N and C termini revealing a novel molecular mechanism for androgen receptor antagonists.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15598662&dopt=Abstract• “AR antagonists such as bicalutamide that are currently in use for prostate cancer treatment can also mediate NCoR recruitment, but mifepristone (RU486) at nanomolar concentrations is unique in its ability to markedly enhance the AR-NCoR interaction. The RU486-liganded AR interacted with a C-terminal fragment of NCoR, and this interaction was mediated by the two most C-terminal nuclear receptor interacting domains (RIDs) present in NCoR.”

2005: Effects of mifepristone on the proliferation£¬ apoptosis and cis-diamminedichloroplatinum sensitivity of cultured chemoresistant human ovarian cancer cellshttp://www.cmj.org/Periodical/PaperList.asp?id=LW7763• “In conclusion, the present study provides evidence that mifepristone has dose dependent anti-proliferative effects on chemoresistant human ovarian cells, and enhance their CDDP-sensitivity. This may be associated with the synergistic effect between mifepristone and CDDP in inducing apoptosis and G0/G1-phase stasis. Further study should be carried out to explore the optimum protocol for clinical use of CDDP and mifepristone.”

2005: Management of patients receiving long-term treatment with mifepristone.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16359971&itool=iconabstr&query_hl=35&itool=pubmed_docsum• “Mifepristone (200 mg daily). One patient received treatment for more than 13 years; six received treatment for 10-12 years; five received treatment for 4-9 years; eight received treatment for 1-4 years; and the remainder received treatment for 4-10 months. Mifepristone can be administered for prolonged periods. Ultrasound should be performed if irregular vaginal bleeding occurs. In asymptomatic women, it should be performed annually. If endometrial thickening is observed, then endometrial biopsy is recommended. Because biochemical hypothyroidism has been reported during long-term mifepristone therapy, thyroid function tests should be performed annually.”